%0 Journal Article
%T mTOR Inhibition: From Aging to Autism and Beyond
%A Matt Kaeberlein
%J Scientifica
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/849186
%X The mechanistic target of rapamycin (mTOR) is a highly conserved protein that regulates growth and proliferation in response to environmental and hormonal cues. Broadly speaking, organisms are constantly faced with the challenge of interpreting their environment and making a decision between ¡°grow or do not grow.¡± mTOR is a major component of the network that makes this decision at the cellular level and, to some extent, the tissue and organismal level as well. Although overly simplistic, this framework can be useful when considering the myriad functions ascribed to mTOR and the pleiotropic phenotypes associated with genetic or pharmacological modulation of mTOR signaling. In this review, I will consider mTOR function in this context and attempt to summarize and interpret the growing body of literature demonstrating interesting and varied effects of mTOR inhibitors. These include robust effects on a multitude of age-related parameters and pathologies, as well as several other processes not obviously linked to aging or age-related disease. 1. Introduction mTOR regulates a diverse array of cellular processes through its catalytic function as a serine/threonine protein kinase of the phosphoinositide-3-kinase-related family [1]. It acts within at least two distinct molecular complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [2]. The composition of each complex is highly studied, and many of the distinct components of each complex have been characterized [3, 4]. mTORC1 consists of mTOR, the regulatory-associated protein of mTOR (raptor), the mammalian lethal with Sec13 protein 8 (mLST8), the DEP domain containing mTOR-interacting protein (deptor), and the proline-rich Akt substrate of 40£¿kDa (PRAS40). mTORC2 also contains mTOR and mLST8, but the remaining mTORC2 components are distinct from mTORC1. These include the rapamycin-insensitive companion of mTOR (rictor), protein observed with rictor (protor), mammalian stress-activated protein kinase-interacting protein 1 (mSin1), and proline-rich protein 5 (PRR5). Both mTOR complexes are essential, as loss of either raptor or rictor results in loss of viability [5, 6]. mTOR was first identified from studies in the budding yeast Saccharomyces cerevisiae of mutations that conferred altered sensitivity to the macrolide antibiotic rapamycin (also known as sirolimus) [7, 8]. Analysis of rapamycin resistant mutants led to the identification of two yeast genes, TOR1 and TOR2, that both encode mTOR kinases. Yeast Tor1 is found exclusively in mTORC1, while yeast Tor2 functions in both mTOR complexes. Thus,
%U http://www.hindawi.com/journals/scientifica/2013/849186/